Our major goal is to improve survival for all patients who require unrelated donor (URD) transplantation through a better understanding of the HLA barrier. HLA mismatching is associated with increased risks of GVHD and mortality. We recently found that survival after HLA-mismatched URD transplantation is superior when the mismatched alleles are evolutionarily related (clade-matched) and are expressed at low levels than when they are evolutionarily different (clade-mismatched) and expressed at high levels. These data suggest a novel approach for defining permissible HLA mismatches. At the same time, HLA matching does not guarantee that risks will never occur. We have new evidence that variation in the HLA-DP 3' untranslated region (UTR) may help explain risks of GVHD after HLA-matched transplantation, supporting a potential role for HLA-DP expression in the etiology of GVHD. Based on our novel findings, we will determine whether clade matching of HLA-A, C and B mismatches is tolerable, and if so, prospectively select clade-matched URDs when matched URDs are not available. We will elucidate the role of HLA-C expression in lowering risks among clade-matches. We furthermore will translate novel SNP information to URD selection to lower GVHD after HLA-matched transplantation, and determine the role for DP expression in GVHD. The specific aims are to 1) determine the significance of clade-mismatching on clinical outcome after HLA-mismatched URD transplantation and 2) determine the role of HLA-DP 3' UTR variation on GVHD risk after HLA-matched URD transplantation. The exploration of permissible HLA mismatches by way of their evolutionary relatedness is a novel approach for understanding all recognition. The integration of MHC region variation into prospective URD selection is a unique approach to improve clinical outcome after transplantation. Elucidation of the role of HLA expression in defining transplant-associated risks will improve understanding of the mechanisms of all recognition. The selection of URDs to lower GVHD and mortality will directly benefit studies described in Project 2, and complement strategies developed by Projects 3 and 4 for lowering relapse.